We have advanced many lines of evidence indicating that the clinical and biochemical manifestations of melancholic depression reflect a concomitant activation of the corticotropin releasing hormone and locus ceruleus-norepinephrine systems that have escaped their usual counter- regulatory mechanisms. To support this hypothetical model, we have shown that a many classes of antidepressants given chronically promote a decrease in PVN CRH mRNA expression, content, and secretion, including not only tricyclic antidepressants (e.g. imipramine) , but also MAO inhibitors (e.g. phenelzine), specific serotonin uptake inhibitors (e.g. fluoxetine), alpha-2 receptor antagonists (e.g. idosoxan), anticonvulsants (e.g. carbamazepine), and GABA agonists (e.g. alprazolam). Clinically, we have shown that both the chronic administration of fluoxetine and electroconvulsive therapy decrease CSF levels of CRH in patients with major depression. Moreover, we have shown that these effects are specific to the resting state of the organism; hence, they are most pronounced in those in whom there is a sustained activation of the PVN CRH neuron, present on either a genetic or environmental basis. Our clinical data show that normal aging is associated with a progressive fall in CSF CRH, while our basic data show that aging in the rat is associated with a progressive central adrenal insufficiency due to a decrease in CRH synthesis and release. These data are in contrast with the progressive increase in plasma cortisol levels and CSF CRH levels seen in patients with a history of melancholia and support the theory that progressive episodes of CRH hypersecretion in melancholia predispose to the exacerbating course of recurrent affective illness. Our data also suggest that while acute glucocorticoid secretion serves to restrain the generalized stress-response from overshooting, chronic glucocorticoid secretion may enhance it, and hence, exacerbate the course of melancholic depression. Specifically, glucocorticoid administration both accelerates the rate of electrically-induced limbic kindling and the effects of limbic kindling on the expression of CRH mRNA in hippocampal GABAergic neurons where CRH is normally not expressed. We have also advanced data that experimentally-induced hyperthyroidism is associated with enhanced CRH mRNA expression and content in the PVN, as well as enhanced CRH release from rat hypothalamic organ cultures. These data are of interest in the light of preliminary data from our group regarding central hyperthyroidism in patients with severe melancholic depression, who also show evidence of hypothalamic, CRH-mediated hypercortisolism.